Dosulepin

Identification

Name

Dosulepin

Accession Number

DB09167

Type

Small Molecule

Groups

Approved

Description

Dosulepin (INN, BAN) formerly known as dothiepin (USAN), is a tricyclic antidepressant with anxiolytic properties that is used in several European and South Asian countries, as well as Australia, South Africa, and New Zealand. It is not FDA-approved due to low therpeutic index and significant toxicity in overdose. Dosulepin inhibits the reuptake of biogenic amines, increasing available neurotransmitter levels at the synaptic cleft. The use of dosulepsin is only recommended in patients who are intolerant or unresponsive to alternative antidepressant therapies. Dosulepsin is a thio derivative of Amitriptyline with a similar efficacy to that of Amitriptyline, and also exhibits anticholinergic, antihistamine and central sedative properties [8].
Its hydrochloride form is a common active ingredient in different drug formulations.

Pharmacology

Indication

Indicated in the treatment of symptoms of depressive illness, especially where an anti-anxiety effect is required.

Structured Indications

Not Available

Pharmacodynamics

Dosulepin is a tricyclic antidepressant that interacts with various receptors and transporters. It is a monoamine reuptake inhibitor with approximately equal potency for noradrenaline and 5-HT that increases the availability of these neurotransmitters at the central synapses [8]. The metabolites of dosulepin are shown to inhibit 5HT uptake by the human blood platelet [2].

Mechanism of action

By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug [5].

Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors [4]. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects [5]. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation [7, 5].
Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation [6]. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect.

Main metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide may also bind to 5HT, α2 and H1 receptors, although with less affinity compared to the parent drug [3].

Dosulepin is well absorbed from the intestines to reach the peak plasma concentration of 37.6ng/mL at 2.18 hours (Tmax) following oral administration of 25mg [7]. The steady state concentrations are variable among individuals due to dynamic relationship between the drug dose and plasma concentration [8].

Volume of distribution

The mean apparent Vd is approximately 45 L/kg after oral administration of 75mg dosulepin [2]. It crosses the blood-brain barrier to mediate its antidepressant actions and also crosses the placental barriers, with low concentration of the drug excreted in breast milk [8].

Dosulepin undergoes extensive hepatic metabolism, to form main metabolites N-demethylated derivative northiaden (desmethyldosulepin or northiaden) and dosulepin S-oxide. Northiaden S-oxide is among 12 basic metabolites that are found in urine. The metabolic pathways of dosulepin is thought to involve N-demethylation, S-oxidation and glucuronic acid conjugation [8].

Dosulepin is predominantly cleared via renal elimination, mainly in the form of metabolites. Renal excretion of dosulepin and its metabolites accounts for 50% - 60% of total elimination, and biliary/fecal excretion is about 15%-40% [7].

Half life

The elimination half life is approximately 20.4 hours following oral administration of 25mg dosulepin [7].

Clearance

Oral clearance is approximately 1.36 L/kg * hr following a single oral dose of 75mg dosulepin [2].

Toxicity

High mortality is associated with overdose of dosulepin (>5mg/kg) with the onset of toxicity occuring within 4-6 hours. Dosulepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse) and severe hypotension, especially in the elderly [7]. Withdrawal symptoms are reported in case of sudden cessation of therapy, which include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration. There have been reports of increased suicidal thoughts or behaviour with dosulepin treatment. Oral lowest published toxic dose (Toxic Dose Low, TDLo) is 90 mg/kg in infants and 4.5 mg/kg in female adults. Intravenous LD50 in mouse is 31 mg/kg [MSDS].